1-alkyl-1-azoniabicyclo&#39; 2.2.2 octane carbamate derivatives and their use as muscarinic receptor antagonists

ABSTRACT

Carbamate of general formula (I), wherein R1, R2, and R3 are H, OH, NO 2 , SH, CN, F, Cl, Br, I, COOH, CONH 2 , (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 4 )-alkylsulfanyl, (C 1 -C 4 )-alkylsulfinyl, (C 1 -C 4 )-alkylsulfonyl, (C 1 -C 4 )-alkoxyl optionally substituted with one or several F, and (C 1 -C 4 )-alkyl optionally substituted with one or several F or OH; R4 is cycloalkyl, phenyl, heteroaryl or a bicyclic ring system; R5 is cycloalkyl, (C 5 -C 10 )-alkyl, a substituted (C 1 -C 10 )-alkyl; and X −  is a physiologically acceptable anion. Carbamate (I) is selective M 3  receptor antagonists versus M 2  receptor and may be used for the treatment of urinary incontinence (particularly, the one caused by overactive bladder), irritable bowel syndrome, and respiratory disorders (particularly, chronic obstructive pulmonary disease, chronic bronchitis, asthma, emphysema, and rhinitis), as well as in ophthalmic interventions.

The present invention relates to novel compounds of type3-alkylphenylcarbamoyloxy-1-alkyl-1-azoniabicyclo[2.2.2]octane, actingas muscarinic receptor antagonists, to the preparation of suchcompounds, and to the use of the same in the prevention and treatment ofdiseases related with respiratory tract, digestive tract, and urinarysystem.

BACKGROUND OF THE ART

It is known that compounds having a muscarinic receptor antagonisteffect induce bronchodilation, gastrointestinal motility inhibition,gastric acid secretion reduction, dry mouth, mydriasis, tachycardia, aswell as urinary bladder contraction inhibition.

Between 1983 and 1993, continuous advances were produced in theknowledge of muscarinic receptor pharmacology. During this period, atotal of five human genes codifying muscarinic receptor subtypes (m1,m2, m3, m4and m5) were cloned and expressed, which encoded fivefunctional receptors (M₁, M₂, M₃, M₄ and M₅).

The M₁ receptor is a postsynaptic neuronal receptor mainly located inbrain and peripheral parasympathetic glands. In smooth cardiac musclethere is a major population of M₂ receptors. The M₃ receptor ispredominantly located in glandular exocrine tissues such as salivaryglands. The M₄ receptor is mainly present in cerebral cortex, striatumand some peripheral locations in specific species. The M₅ receptor hasbeen described in the cerebral vessels. In the smooth muscle ofintestinal tract, urinary bladder and bronchus, M₂ and M₃ receptorscoexist. Nevertheless, functional information commonly acceptedindicates that the M₃ receptor is the responsible for the contractileeffect of the endogenous neurotransmitter in the last three tissues.

Few M₃ antagonists lacking M₂ affinity have been developed. The presentinvention contributes to fill this need by providing this kind ofantagonists.

It seems interesting to obtain M₃ receptor selective antagonists toavoid the adverse effects due to blockade of other muscarinic receptors,mainly the cardiac effects due to M₂ receptor inhibition. At present,oxybutynin (Alza), trospium (Madaus) and tolterodine (Pharmacia), amongothers, are commercially available compounds showing reduced selectivityfor M₂ and M₃ receptors. However, darifenacin (Pfizer), and solifenacin(Yamanouchi), both in clinical phase, exhibit M₃ antagonist activitywith a reduced affinity towards M₂ receptor.

In contrast, tiotropium bromide (Böehringer Ingelheim) binds withsimilar affinity to muscarinic M₃ and M₂ receptors. However, itdissociates more slowly from M₃ than from M₂ receptors and subsequentlyhas a long acting effect over M₃ receptor. In consequence, it may beconsidered as a functionally selective M₃ antagonist compound.

The following are some patent applications claiming compounds withcarbamic structures as selective M₃ receptor antagonists: JP 04/95071,WO 9506635, EP 747355, EP 801067 and WO 0200652. All these documentsdescribe carbamates different to those described in the presentinvention, and the later two describe the structurally nearest to thehereby claimed. In document WO 0104118 some alkylquinuclidinium estersare described as selective antagonist for M₃ receptors, but they arealso different from the compounds claimed in the present invention.

The compounds claimed in the present invention may be used either aloneor in association with other therapeutic agents selected from the groupconsisting of: calcium channel blockers, α-adrenoceptor antagonists,β₂-agonists, dopamine agonists, corticosteroids, phosphodiesterase 4inhibitors, leukotriene D4 antagonists, endothelin antagonists,substance-P antagonists, antitussives, decongestants, histamine H₁antagonists, 5-lipooxigenase inhibitors, VLA-4 antagonists andtheophylline.

SUMMARY OF THE INVENTION

An aspect of the present invention relates to the provision of newalkylquinuclidinium carbamates of general formula (I)

and prodrugs, individual isomers, racemic or non-racemic mixtures ofisomers, pharmaceutically acceptable salts, polymorphs and solvatesthereof,

-   -   wherein R1, R2 and R3 are radicals independently selected from        the group consisting of H, OH, NO₂, SH, CN, F, Cl, Br, I, COOH,        CONH₂, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,        (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkoxyl        optionally substituted with one or several F, and, (C₁-C₄)-alkyl        optionally substituted with one or several F or OH;        alternatively, either R1 and R2, or R2 and R3 may be forming a        biradical selected from the group consisting of —CH₂—CH₂—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—;    -   R4 is a radical selected from the group consisting of:        -   a) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,            cyclohexenyl, norbornenyl, bicyclo[2.2.1]heptanyl, and 1-,            2-naphtyl, all of them optionally substituted with one or            several substituents independently selected from the group            consisting of OH, oxo (═O), SH, NO₂, CN, F, Cl, Br, I,            CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,            (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl            optionally substituted with one or several F or OH, and            (C₁-C₄)-alkoxyl optionally substituted with one or several            F;        -   b) a C-linked radical of a five or six membered heterocyclic            ring containing at least one heteroatom selected from the            group consisting of O, S, and N, being this heterocyclic            ring optionally substituted with one or several substituents            independently selected from the group consisting of OH, oxo            (═O), SH, NO₂, CN, F, Cl, Br, I, CONH₂, COOH,            (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,            (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl            optionally substituted with one or several F or OH, and            (C₁-C₄)-alkoxyl optionally substituted with one or several            F;        -   c) a C-linked radical of a bicyclic ring system consisting            of a phenyl ring fused to a five or six membered            heterocyclic ring containing at least one heteroatom            selected from the group consisting of O, S and N, being this            bicyclic ring system optionally substituted with one or            several substituents independently selected from the group            consisting of OH, oxo (═O), SH, NO₂, CN, F, Cl, Br, I,            CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,            (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl            optionally substituted with one or several F or OH, and            (C₁-C₄)-alkoxyl optionally substituted with one or several            F; and        -   d) phenyl optionally substituted with one or several            substituents independently selected from the group            consisting of OH, SH, NO₂, CN, F, Cl, Br, I, CONH₂, COOH,            (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,            (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl            optionally substituted with one or several F or OH, and            (C₁-C₄)-alkoxyl optionally substituted with one or several            F;    -   R5 is a radical selected from the group consisting of:        -   a) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, all of            them optionally substituted with one or several substituents            independently selected from the group consisting of OH, oxo            (═O), SH, NO₂, CN, F, Cl, Br, I, CONH₂, NR7CO—(C₁-C₄)-alkyl,            COOH, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,            (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl            optionally substituted with one or several F or OH, and            (C₁-C₄)-alkoxyl optionally substituted with one or several            F;        -   b) (C₅-C₁₀)-alkyl;        -   c) (C₁-C₁₀)-alkyl substituted with one or several radicals            independently selected from the group consisting of R6,            COR6, NH₂, NR6R7, CONR6R7, NR7COR6, OH, OR6, COOR6, OCOR6,            SO₂R6, SH, SR6, SOR6, COSR6, SCOR6, CN, F, Cl, Br, NO₂,            cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,            cyclohexenyl, norbornenyl, and bicyclo[2.2.1]heptanyl;    -   R6 is a radical selected from the group consisting of:        -   a) (C₁-C₅)-alkyl, cyclopropyl, cyclobutyl, cyclopentyl,            cyclohexyl, cyclohexenyl, norbornenyl,            bicyclo[2.2.1]heptanyl, all of them optionally substituted            with one or several substituents independently selected from            the group consisting of OH, oxo (═O), SH, NO₂, CN, F, Cl,            Br, I, CONH₂, NR7CO—(C₁-C₄)-alkyl, COOH,            (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,            (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl            optionally substituted with one or several F or OH, and            (C₁-C₄)-alkoxyl optionally substituted with one or several            F;        -   b) phenyl optionally substituted with one or several            substituents independently selected from the group            consisting of OH, SH, NO₂, CN, F, Cl, Br, I, CONH₂,            NR7CO—(C₁-C₄)-alkyl, COOH, (C₁-C₄)-alkoxycarbonyl,            (C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl,            (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionally substituted            with one or several F or OH, and (C₁-C₄)-alkoxyl optionally            substituted with one or several F;        -   c) a C-linked radical of a five or six membered heterocyclic            ring containing at least one heteroatom selected from the            group consisting of O, S, and N, being this heterocyclic            ring optionally substituted with one or several substituents            independently selected from the group consisting of OH, oxo            (═O), SH, NO₂, CN, F, Cl, Br, I, CONH₂, NR7CO—(C₁-C₄)-alkyl,            COOH, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,            (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl            optionally substituted with one or several F or OH, and            (C₁-C₄)-alkoxyl optionally substituted with one or several            F; and        -   d) a C-linked radical of a bicyclic ring system consisting            of a phenyl ring fused to a five or six membered            heterocyclic ring containing at least one heteroatom            selected from the group consisting of O, S and N, being this            bicyclic ring system optionally substituted with one or            several substituents independently selected from the group            consisting of OH, oxo (═O), SH, NO₂, CN, F, Cl, Br, I,            CONH₂, COOH, NR7CO—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxycarbonyl,            (C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl,            (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionally substituted            with one or several F or OH, and (C₁-C₄)-alkoxyl optionally            substituted with one or several F;    -   R7 is a radical selected from the group consisting of H,        phenoxycarbonyl, benzyloxycarbonyl, (C₁-C₄)-alkoxycarbonyl,        (C₁-C₄)-alkylcarbonyl, (C₁-C₄)-alkylsulfonyl, and (C₁-C₅)-alkyl;        and    -   X⁻ is a physiologically acceptable anion, such as chloride,        bromide, iodide, hydroxide, sulfate, nitrate, phosphate,        acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate,        succinate, mandelate, methanesulfonate and p-toluenesulfonate.

In a particular embodiment, R4 is 2-thiophene, 3-thiophene or phenyl,all of three cases optionally substituted with one or severalsubstituents independently selected from the group consisting of OH, SH,NO₂, CN, F, Cl, Br, I, CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl,(C₁-C₄)-alkyl optionally substituted with one or several F or OH, and(C₁-C₄)-alkoxyl optionally substituted with one or several F.

In another particular embodiment R5 is a (C₁-C₅)-alkyl substituted withone radical selected from the group consisting of R6, COR6, NR6R7,CONR6R7, NR7COR6, OR6, COOR6, OCOR6, SR6, SOR6, SO₂R6; and

-   -   R6 is a radical selected from the group consisting of:        -   a) phenyl optionally substituted with one or several            substituents selected from the group consisting of OH, SH,            CN, F, Cl, Br, I, CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl,            (C₁-C₄)alkylsulfanyl, (C₁-C₄)-alkylsulfinyl,            (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionally substituted            with one or several F or OH, and (C₁-C₄)-alkoxyl optionally            substituted with one or several F;        -   b) a C-linked radical of a five or six membered heterocyclic            ring containing at least one heteroatom selected from the            group consisting of O, S, and N, being this heterocyclic            ring optionally substituted with one or several substituents            independently selected from the group consisting of OH, SH,            NO₂, CN, F, Cl, Br, I, CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl,            (C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl,            (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionally substituted            with one or several F or OH, and (C₁-C₄)-alkoxyl optionally            substituted with one or several F.

Another aspect of the present invention relates to new intermediatecompound of formula (X)

and prodrugs, individual isomers, racemic or non-racemic mixtures ofisomers, pharmaceutically acceptable salts, polymorphs and solvatesthereof,

-   -   for the preparation of a compound of formula (I) as defined in        claim 1,    -   wherein R1, R2, R3, R8 and R9 are radicals independently        selected from the group consisting of H, OH, NO₂, SH, CN, F, Cl,        Br, I, CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl,        (C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl,        (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkoxyl optionally substituted        with one or several F, (C₁-C₄)-alkyl optionally substituted with        one or several F or OH, except when R8 and R9 are H;        alternatively, either R1 and R2, or R2 and R3 may be forming a        biradical selected from the group consisting of —CH₂—CH₂—CH₂—,        and —CH₂—CH₂—CH₂—CH₂—.

In still another particular embodiment of the present invention theconfiguration of the 3 position in the quinuclidine ring of all thepreceding compounds is (R).

In cases where compounds of formula (I) have an asymmetric carbon, theracemic mixtures thereof may be resolved in their enantiomers byconventional methods, such as separation by column chromatography withchiral stationary phase or by fractioned crystallization of theirdiasteroisomeric salts. The later may be prepared by reaction withenantiomerically pure acids or bases. Chiral compounds of formula (I)may also be obtained by enantioselective synthesis through chiralprecursors.

The present invention also relates to physiologically acceptable saltsof carbamates of general structure (I). In this specification“physiologically acceptable salts” means salts that are pharmaceuticallyacceptable, and that possess the desired pharmacological activity of theparent compound.

Such salts include:

-   -   Acid addition salts formed with inorganic acids such as        hydrochloric, hydrobromic, nitric, sulfuric, and phosphoric        acids, as well as with organic acids such as acetic,        benzenesulfonic, benzoic, camphorsulfonic, mandelic,        methanesulfonic, oxalic, succinic, fumaric, tartaric and maleic        acids.    -   Salts formed when an acidic proton present in the parent        compound either is replaced by a metal ion, e.g., an alkali        metal ion, an alkaline earth ion, or an aluminum ion; or        coordinates with an organic or inorganic base. Acceptable        organic bases include diethylamine, and triethylamine.        Acceptable inorganic bases include aluminium hydroxide, calcium        hydroxide, potassium hydroxide, sodium carbonate and sodium        hydroxide.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) of the same acid addition salt.

In this specification the terms ‘alkyl’ and ‘alkoxyl’ includes straightchained and branched structures.

Compounds of general structure (I) may be obtained from intermediates ofgeneral formula (IV), which may be prepared by three general methods(namely, A, B and C) represented in the scheme below.

Starting arylalkylamines (II) are commercially available, or may beobtained by known methods in the literature such as alkylation ofanilines, reductive amination, or reduction of anilides.

According to Method A, acylation of the arylalkylamine (II) through achloroformate (e.g. methylchloroformate, ethylchloroformate or4-nitrophenylchloroformate) in an inert solvent [e.g. dimethylformamide(DMF), dichloromethane (DCM), 1,2-dichloroethane (1,2-DCE),tetrahydrofurane (THF) or toluene] is carried out first, at atemperature ranging from 0° C. to the reflux temperature of the solvent.In some cases, it is advisable to carry out the reaction using thecorresponding chloroformate as solvent, or using a base such as atertiary amine or potassium carbonate. Then, the alkoxylic moiety isintroduced by a transesterification reaction between the carbamateintermediate (III) and 3-quinuclidol, using a base such as sodium metal,sodium hydride, or sodium methoxide. The reaction may be carried out ata temperature ranging from 0° C. to the reflux temperature of thesolvent.

According to Method B, 3-quinuclidol is first reacted with achloroformate (e.g. trichloromethylchloroformate) in an inert solvent(e.g. DMF, DCM, 1,2-DCE) at a temperature ranging from 0° C. to thereflux temperature of the solvent in order to obtain the correspondinghydrochloride of quinuclidol chloroformate. Then, arylalkylamine (II) isacylated with quinuclidol chloroformate. The reaction is carried out inan inert solvent (e.g. DMF, DCM, CHCl₃, 1,2-DCE) at a temperatureranging from 20° C. to the reflux temperature of the solvent.

According to Method C, 3-quinuclidol is first reacted with acarbonyldiimidazole (DCI) in an inert solvent (e.g. DCM, 1,2-DCE) atroom temperature in order to obtain the correspondingimidazole-1-carboxylic acid 1-azabicyclo[2.2.2]oct-3-yl ester. Then,arylalkylamine (II) is metalated in an inert solvent (e.g. THF) usingBuLi and the ester was added at a temperature ranging from 0° C. to roomtemperature.

The quaternary ammonium salt of general formula (I), may be prepared byan N-alkylation reaction between an alkylating reagent (R5-X) and acompound of general formula (IV), using an inert solvent [e.g. DMF, DCM,CHCl₃, 1,2-DCE, CH₃CN (acetonitrile)] at a temperature ranging from 20°C. to the reflux temperature of the solvent.

The R5-X compounds are either commercially available or may be preparedby known methods, such as those illustrated below.

Additionally, when R5 is —CH₂—CHOH-A, wherein A is any radical except H,the quaternary amonium salt of general formula (I) may be prepared byalkylation between an epoxide and a compound of general formula (IV), inan inert solvent (e.g. DMF, DCM, CHCl₃, 1,2-DCE, CH₃CN) at a temperatureranging from 20° C. to the reflux temperature of the solvent.

The compounds of the present invention are selective M₃ receptorantagonists versus M₂ receptor. For this reason they may be used for thetreatment of urinary incontinence (particularly, the one caused byoveractive bladder), irritable bowel syndrome, and respiratory disorders(particularly, chronic obstructive pulmonary disease, chronicbronchitis, asthma, emphysema, and rhinitis), as well as in ophthalmicinterventions.

Thus, another aspect of the present invention is the use of carbamatesof formula (I) for the preparation of medicaments for the treatment ofthe following diseases: urinary incontinence, particularly when it iscaused by overactive bladder; irritable bowel syndrome; respiratorydisorders, especially chronic obstructive pulmonary disease, chronicbronchitis, asthma, emphysema, and rhinitis. Furthermore, their use forthe preparation of a medicament for ophthalmic interventions, is alsoforming part of this aspect of the invention.

Binding Test to Human M₂ and M₃ Muscarinic Receptors

The following tests show the M₃ antagonist activity of compounds offormula (I), as well as their selectivity towards the M₂ receptor. Someresults obtained for cloned human muscarinic M₂ and M₃ receptors arelisted, and the used methodology is described.

Membranes from CHO—K1 cells transfected with human M₂ or M₃ receptorswere used. The summarised experimental procedure for both receptors wasthe following: cell membranes (15-20 μg) were incubated with [³H]-NMS(0.3-0.5 nM) for 60 min at 25° C., in presence or absence of theantagonists. Incubation was carried out in 96 wells polystyrenemicroplates in a total incubation volume of 0.2 mL of PBS pH 7.4. Nonspecific binding was determined in parallel assays in presence ofatropine (5 μM). Samples were filtered through type GF/C glass fibre,preincubated with PEI 0.3%. Filters were washed 3-4 times with 50 mMTris-HCl, 0.9% NaCl, pH 7.4 at 4° C., and dried at 50° C. for 45 min.Filter bound radioactivity was quantified by liquid scintillationcounting.

For the calculation of the inhibition constant (K_(i)), displacementcurves were analysed by non-linear regression (GraphPad Prism).Dissociation constant (K_(d)) of [³H]-NMS for each receptor was obtainedthrough the saturation curves obtained in the same conditions as theexperiments carried out with the corresponding antagonists. The resultsobtained, expressed as the mean of two independent experiments, eachperformed in duplicate, are shown in the table below. M₂/M₃ ratiosgreater than 1 indicates a M₃ selective activity.

M₃ M₂/M₃ (k_(i), nM) (ratio) OXYBUTYNIN 2.04 3 TOLTERODINE 10.20 1DARIFENACIN 2.97 56 SOLIFENACIN 8.30 10 Int. 29 0.02 105 Int. 32 0.15 23Ex. 11 0.34 80 Ex. 50 0.06 345 Ex. 69 0.02 32

EXAMPLES

The invention will be illustrated by the following non-limitingexamples.

The structure of the different compounds was confirmed by ¹H-NMR,recorded using a Varian GEMINI-200 or Gemini-300 MHz instruments andchemical shifts are expressed as ppm (δ) from the internal referenceTMS. The nomenclature used in this document is based on AUTONOM(Automatic Nomenclature), a Beilstein Institute computerized system forthe generation of IUPAC systematic nomenclature.

Intermediate 1: (R)-3-quinuclidyl chloroformate, hydrochloride

To a solution of 8.7 mL (74.8 mmol) of trichloromethyl chloroformate in240 mL of dichloromethane, a solution of 4.75 g (37.4 mmol) of(R)-3-quinuclidol in 240 mL of dichloromethane was added dropwise at 0°C. under inert atmosphere and with continuous stirring. Then, themixture was stirred at room temperature for 24 h, and the solvent wasdistilled off under reduced pressure to give 8.46 g (37.4 mmol) of awhite solid corresponding to the title compound. IR (KBr, cm⁻¹): 3380,2650-2500, 1776.

Intermediate 2: (R)-Imidazole-1-Carboxylic acid1-azabicyclo[2.2.2]oct-3-yl ester

To a suspension of 20.0 g (157 mmol) of (R)-3-quinuclidol in 400 mL ofdichloromethane, 31.55 g (189 mmol) of DCl were added at roomtemperature. The yellow solution was stirred during 4 hrs under inertatmosphere. Then, 340 mL of water were added. The organic layer wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained solid was crystallized with isopropylacetate (IPAC)-heptane to give 23.5 g (68%) of the title compound. IR(KBr, cm⁻¹): 1746.

Intermediate 3: (R)-Benzylphenylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester hydrochloride

Method A

To a solution of 5.1 g (20 mmol) of benzylphenylcarbamic acid ethylester (Dannley, L. J. Org. Chem. 1957, 22, 268) and 7.63 g (60 mmol) of3-quinuclidol in 120 mL of toluene, 800 mg (20 mmol) of sodium hydride(60% dispersion in oil) were added and the mixture was refluxed forthree hours. During this time toluene was added to replace the distilledvolume. The reaction crude was allowed to cool down, and was dilutedwith toluene (250 mL), washed with water and dried over anhydrous sodiumsulfate. Then, the solvent was distilled off under reduced pressure. Theobtained oil was treated at room temperature with hydrogen chloridesaturated ethanol, the solvent was distilled off, and the obtained solidwas broken up with a 1:1 ethyl acetate/diethyl ether mixture to give 230mg (0.6 mmol) of a white solid corresponding to the title compound(m.p.: 54° C.).

Method B

To a suspension of 750 mg (2.58 mmol) of 3-quinuclidyl chloroformatehydrochloride in 20 mL of 1,2-DCE, a solution of 395 mg (2.15 mmol) ofN-phenylbenzylamine in 5 mL of 1,2-DCE was added dropwise. Oncecompleted the addition, the mixture was refluxed for three hours. Thereaction crude was allowed to cool down and the solvent distilled offunder reduced pressure. The residue was purified by columnchromatography (SiO₂, eluent: CHCl₃-methanol 10:1) yielding 720 mg (1.95mmol) of a hygroscopic foam corresponding to the title compound. IR(KBr, cm⁻¹): 3400-3200, 2700-2300, 1700 cm⁻¹. ¹H-RMN (CDCl₃): 12.30 (s,1H), 7.20-6.90 (m, 10H), 5.10 (m, 1H), 4.83 (m, 2H), 3.52 (m, 1H), 3.18(m, 4H), 2.80 (m, 1H), 2.34 (s, 1H), 1.92 (m, 2H), 1.60 (m, 2H).

Method C

To a solution of 2.73 g (14.9 mmol) of N-phenylbenzylamine in 20 mL ofTHF, previously cooled at −10° C., 5.96 mL of n-BuLi (2.5 M) were addeddropwise. At −10° C. 3.29 g (14.9 mmol) of intermediate 2 in 35 mL ofTHF were slowly added. The resulting mixture was stirred for 2 h andallowed to rise room temperature, then 35 mL of water was added. Thesolution was extracted with ethyl acetate, and the organic phase wasdried over anhydrous sodium sulfate and the solvent was removed underreduced pressure. The residue was dissolved in EtOH/HCl and the solventevaporated again. The new residue was purified by column chromatography(eluent: chloroform-methanol 10:1) yielding 1.53 g of an hygroscopicfoam corresponding to the title compound. IR (KBr, cm⁻¹): 3400-3200,2700-2300,1700 cm⁻¹.

The following intermediates (4 to 15) were prepared using method B,described in the patent application WO 0200652:

-   Intermediate 4: (R)-Benzyl-m-tolylcarbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 5: (R)-Benzyl-(3-fluorophenyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 6: (R)-(4-Fluorobenzyl)phenylcarbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 7: (R)-(4-Fluorobenzyl)-m-tolylcarbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 8: (R)-(4-Fluorobenzyl)-(2-fluorophenyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 9: (R)-(4-Fluorobenzyl)-(3-fluorophenyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 10: (R)-(3,4-Difluorobenzyl)phenylcarbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 11: (R)-(3,4-Difluorobenzyl)-m-tolylcarbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 12: (R)-(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamic    acid 1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 13: (R)-(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamic    acid 1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 14:    (R)-(2-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 15:    (R)-(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride.-   Intermediate 16:    (R)-3-Cyclohexylmethylphenylcarbamoyloxy-1-azoniabicyclo[2.2.2]octane;    hydrochloride

The following new intermediates were prepared using any of the methodsdescribed above:

Intermediate 17: (R)-Thiophen-2-ylmethyl-m-tolylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester

¹H-NMR (CDCl₃): 7.25 (d, 1H), 7.22 (d, 1H), 7.06 (d, 1H), 6.94 (m, 1H),6.91 (dd, 2H), 6.84 (dd, 1H), 4.95 (s, 2H), 4.88 (m, 1H), 3.32 (dd, 1H),3.10-2.60 (m, 5H), 2.31 (s, 3H), 2.14 (m, 1H), 1.80-1.30 (m, 4H).

Intermediate 18: (R)-(2-Fluorophenyl)thiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester

¹H-NMR (CDCl₃): 7.35-7.20 (m, 2H), 7.15-7.00 (m, 3H), 6.86 (m, 2H), 4.95(s, 2H), 4.82 (m, 1H), 3.22 (m, 1H), 3.15-2.50 (m, 5H), 2.01 (m, 1H),1.80-1.50 (m, 2H), 1.45-1.20 (m, 2H).

Intermediate 19: (R)-(3-Fluorophenyl)thiophen-2-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.35-7.20 (m, 2H), 7.15-7.00 (m, 3H), 6.86 (m, 2H), 4.95(s, 2H), 4.82 (m, 1H), 3.22 (m, 1H), 3.15-2.50 (m, 5H), 2.01 (m, 1H),1.80-1.50 (m, 2H), 1.45-1.20 (m, 2H).

Intermediate 20: (R)-(3-Methylthiophen-3-ylmethyl)phenylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 11.69 (br, 1H), 7.29 (m, 3H), 7.17-6.90 (m, 3H), 6.71(dd, 1H), 5.08 (m, 1H), 4.89 (s, 2H), 3.61 (m, 1H), 3.40-2.60 (m, 5H),2.37 (m, 1H), 2.19-1.80 (m, 3H), 1.87 (s, 3H), 1.61 (m, 1H).

Intermediate 21:(R)-3-[(4-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane:hydrochloride

¹H-NMR (CDCl₃): 7.42-7.30 (m, 3H), 7.15 (d, 1H), 7.08 (br, 2H), 6.79 (d,1H), 5,30 (br, 1H), 5.04 (m, 1H), 4.90 (s, 2H), 3.55-3.40 (m, 1H),3.20-2.95 (m, 4H), 2.80 (br, 1H), 2.32 (m, 1H), 2.00-1.65 (m, 2H), 1.59(m, 2H).

Intermediate 22: (R)-(5-Methylthiophen-2-ylmethyl)phenylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 12.20 (br, 1H), 7.40-7.28 (m, 3H), 7.16-6.90 (br, 2H),6.59 (d, 1H), 6.53 (d, 1H), 5.09 (m, 1H), 4.85 (s, 2H), 3.53 (br, 1H),3.35-3.00 (m, 4H), 2.82 (br, 1H), 2.45 (s, 3H), 2.39 (m, 1H), 2.10-1.55(m, 4H).

Intermediate 23:(R)-(5-Chlorothiophen-2-ylmethyl)-(2-fluorophenyl)carbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.40-7.27 (m, 1H), 7.23-7.05 (m, 3H), 6.71 (d, 1H), 6.60(d, 1H), 5.07 (m, 1H), 4.81 (s, 2H), 3.49 (m, 1H), 3.30-3.00 (m, 4H),2.87 (m, 1H), 2.39 (m, 1H), 2.00-1.80 (m, 2H), 1.75-1.53 (m, 2H).

Intermediate 24: (R)-(5-Bromothiophen-2-ylmethyl)phenylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.42-7.29 (m, 3H), 7.12-7.00 (m, 2H), 6.86 (d, 1H), 6.59(d, 1H), 5.30 (br, 1H), 5.04 (m, 1H), 4.86 (s, 2H), 3.50-3.35 (m, 1H),3.20-2.90 (m, 4H), 2.80 (br, 1H), 2.32 (m, 1H), 2.00-1.65 (m, 3H), 1.59(m, 1H).

Intermediate 25: (R)-(5-Bromothiophen-2-ylmethyl)-m-tolylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.21 (d, 1H), 7.11 (d, 1H), 6.95-6.80 (m, 2H), 6.86 (d,1H), 6.60 (d, 1H), 5.03 (m, 1H), 4.84 (s, 2H), 3.50-3.35 (m, 1H),3.20-2.95 (m, 4H), 2.80 (br, 1H), 2.34 (m, 1H), 2.34 (s, 3H), 2.00-1.60(m, 4H).

Intermediate 26: (R)-(3-Fluorophenyl)thiophen-3-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 8.14 (br, 1H), 7.38-7.24 (m, 2H), 7.08 (d, 1H),6.99-6.92 (m, 4H), 5.07 (m, 1H), 4.81 (s, 2H), 3.65 (ddd, 1H), 3.27-3.08(m, 4H), 2.90 (q, 1H), 2.31 (m, 1H), 2.10-1.80 (m, 2H), 1.70-1.55 (m,2H).

Intermediate 27:(R)-(2-Fluorophenyl)-(3-methylthiophen-2-ylmethyl)carbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.31 (m, 1H), 7.13 (d, 1H), 7.10-6.92 (m, 2H), 7.07 (d,1H), 6.72 (d, 1H), 5.11 (m, 1H), 4.87 (m, 2H), 3.51 (m, 1H), 3.35-2.98(m, 4H), 2.85 (m, 1H), 2.42 (m, 1H), 1.93 (s, 3H), 2.10-1.50 (m, 4H).

Intermediate 28:(R)-(2-Fluorophenyl)-(5-methylthiophen-2-ylmethyl)carbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.31 (m, 1H), 7.20-7.04 (m, 3H), 6.59 (d, 1H), 6.53 (dd,1H), 5.09 (m, 1H), 4.80 (m, 2H), 3.53 (m, 1H), 3.37-3.00 (m, 4H), 2.86(br, 1H), 2.45 (s, 3H), 2.44 (m, 1H), 2.10-1.55 (m, 4H).

Intermediate 29:(R)-(5-Chlorothiophen-2-ylmethyl)-(3-fluorophenyl)carbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.34 (td, 1H), 7.04 (td, 1H), 6.95-6.78 (m, 2H), 6.73(d, 1H), 6.62 (d, 1H), 5.09 (m, 1H), 4.83 (s, 2H), 3.52 (m, 1H),3.35-3.05 (m, 4H), 2.93 (br, 1H), 2.41 (m, 1H), 2.10-1.55 (m, 4H).

Intermediate 30: (R)-(5-Ethylthiophen-2-ylmethyl)-m-tolylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.40-7.28 (m, 3H), 7.15-7.02 (m, 2H), 6.61 (d, 1H), 6.57(d, 1H), 5.12 (m, 1H), 4.87 (s, 2H), 3.55-3.35 (m, 1H), 3.20-2.95 (m,4H), 2.80 (q, 2H), 2.80-2.70 (m, 1H), 2.35 (m, 1H), 2.00-1.55 (m, 4H),1.28 (t, 3H).

Intermediate 31: (R)-Phenylthiophen-3-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.35-7.24 (m, 4H), 7.12-6.92 (m, 2H), 7.03 (d, 1H), 6.96(dd, 1H), 5.01 (m, 1H), 4.77 (s, 2H), 3.48 (ddd, 1H), 3.25-2.97 (m, 4H),2.80 (m, 1H), 2.27 (m, 1H), 2.01-1.77 (m, 2H), 1.65-1.45 (m, 2H).

Intermediate 32: (R)-Thiophen-3-ylmethyl-m-tolylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.27 (dd, 1H), 7.18 (t, 1H), 7.06 (d, 1H), 7.04 (s, 1H),6.97 (dd, 1H), 6.82 (br, 2H), 5.03 (m, 1H), 4.76 (s, 2H), 3.50 (m, 1H),3.28-2.98 (m, 4H), 2.83 (m, 1H), 2.30 (s, 3H), 2.30 (m, 1H), 2.05-1.75(m, 2H), 1.70-1.50 (m, 2H).

Intermediate 33: (R)-(2-Fluorophenyl)thiophen-3-ylmethylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

¹H-NMR (CDCl₃): 7.38-7.20 (m, 2H), 7.11 (d, 1H), 7.10-6.95 (m, 2H), 7.05(s, 1H), 6.99 (dd, 1H), 5.02 (m, 1H), 4.78 (dd, 2H), 3.48 (m, 1H),3.30-2.95 (m, 4H), 2.83 (m, 1H), 2.29 (m, 1H), 2.05-1.80 (m, 2H),1.70-1.50 (m, 2H).

The following new intermediates were also prepared using any of themethods described above, and they have been identified by ¹H-NMR:

-   (R)-(3-Fluorophenyl)-(3-methylthiophen-2-ylmethyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-3-(4-Bromothiophen-2-ylmethyl)-m-tolylcarbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-(4-Bromothiophen-2-ylmethyl)-(2-fluorophenyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-(4-Bromothiophen-2-ylmethyl)-(3-fluorophenyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-(3-Fluorophenyl)-(5-methylthiophen-2-ylmethyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-(5-Chlorothiophen-2-ylmethyl)phenylcarbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-(5-Bromothiophen-2-ylmethyl)-(2-fluorophenyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-(5-Bromothiophen-2-ylmethyl)-(3-fluorophenyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-(5-Ethylthiophen-2-ylmethyl)phenylcarbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-(5-Ethylthiophen-2-ylmethyl)-(2-fluorophenyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride-   (R)-(5-Ethylthiophen-2-ylmethyl)-(3-fluorophenyl)carbamic acid    1-azabicyclo[2.2.2]oct-3-yl ester; hydrochloride

Example 1(R)-3-(Benzylphenylcarbamoyloxy)-1-Cyclopropyl-1-azoniabicyclo[2.2.2]octane;bromide

200 mg (0.59 mmol) of Intermediate 3 and 0.47 mL of bromocyclopropane(0.59 mmol) were mixed in 5 mL of acetonitrile/chloroform (2:3). Theresulting solution was refluxed for 12 hours. The solvent was evaporatedand the residue purified by column chromatography [SiO₂, eluent:dichloromethane-methanol (20:1)] to yield 130 mg (47%) of an hygroscopicwhite solid, corresponding to the title compound. ¹H-NMR (CDCl₃): 7.27(m, 10H), 4.87 (m, 2H), 4.80 (m, 1H), 3.18 (ddd, 1H), 3.01 (m, 1H),2.80-2.50 (m, 5H), 2.23 (m, 1H), 1.98 (m, 2H), 1.65-1.18 (m, 6H).

The following compounds were synthesised according to Example 1:

Example 2(R)-3-(Benzylphenylcarbamoyloxy)-1-(2-Chlorobenzyl)-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 131 mg (45%) as a yellow oil. IR (film, cm⁻¹): 1694.¹H-NMR (CDCl₃): 7.60-7.16 (m, 14H), 5.03 (m, 1H), 4.92 (dd, 2H), 4.80(s, 2H), 4.10 (m, 1H), 3.77 (m, 3H), 3.35 (m. 1H), 2.78 (m, 1H), 2.28(m, 1H), 1.98 (m, 2H), 1.78 (m, 1H), 1.60 (m, 1H).

Example 3(R)-3-(Benzylphenylcarbamoyloxy)-1-(5-methylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-1-azoniabicyclo[2.2.2]octane;chloride,

The yield was 77 mg (53%) as white solid. ¹H-NMR (CDCl₃): 7.27-7.18 (m,10H), 6.97 (t, 2H), 6.82 (dd, 2H), 5.12 (dd, 1H), 4.82 (m, 2H), 4.34 (s,2H), 4.30-4.05 (m, 3H), 4.05-3.70 (m, 4H), 3.05 (dd, 1H), 2.33 (m, 1H),2.10-1.50 (m, 4H).

Example 4(R)-3-(Benzylphenylcarbamoyloxy)-1-ethoxycarbonylmethyl-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 60 mg (35%) as a oil. IR (film, cm⁻¹): 1743, 1701. ¹H-NMR(CDCl₃): 7.28 (m, 10H), 5.15-4.80 (m, 5H), 4.40-3.50 (m, 8H), 2.38 (m,1H), 2.01 (m, 2H), 1.78 (m, 1H), 1.58 (m, 1H), 1.29 (t, 3H).

Example 5(R)-3-(Benzyl-m-tolylcarbamoyloxy)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 120 mg (25%) as white solid. IR (film, cm⁻¹): 1694. ¹H-NMR(CDCl₃): 7.30-6.80 (m, 11H), 6.62 (d, 1H), 5.16 (m, 1H), 4.77 (m, 2H),4.48 (t, 2H), 4.21 (m, 1H), 3.90-3.40 (m, 6H), 3.09 (t, 2H), 2.88 (m,3H), 2.29 (s, 3H), 2.01-1.40 (m, 5H).

Example 6(R)-3-[Benzyl-(3-fluorophenyl)carbamoyloxy]-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 51 mg (16%) as white solid. IR (film, cm⁻¹): 1705. ¹H-NMR(CDCl₃): 7.30-6.90 (m, 10H), 6.80 (d, 1H), 6.68 (d, 1H), 5.17 (m, 1H),4.90 (m, 2H), 4.52 (t, 2H), 4.16 (m, 1H), 3.90-3.60 (m, 5H), 3.41 (m,1H), 3.13 (t, 2H), 2.88 (m, 3H), 2.21-1.60 (m, 5H).

Example 7(R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-(2-m-tolylethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 110 mg (42%) as a yellow solid. ¹H-NMR (CDCl₃): 7.40-7.00(m, 10H), 7.09 (s, 1H), 6.98 (t, 2H), 5.09 (m, 1H), 4.78 (m, 2H), 4.13(m, 1H), 4.00-3.60 (m, 5H), 3.30 (br, 1H), 2.95 (br, 1H), 2.93 (t, 2H),2.33 (m, 1H), 2.30 (s, 3H), 2.10-1.70 (m, 3H), 1.61 (m, 1H).

Example 8(R)-1-[2-(4-Ethoxyphenyl)ethyl]-3-[(4-fluorobenzyl)phenylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 106 mg (38%) as white solid. ¹H-NMR (CDCl₃): 7.40-6.95 (m,11H), 6.79 (d, 2H), 5.06 (m, 1H), 4.78 (m, 2H), 4.15-3.60 (m, 6H), 3.95(q, 2H), 3.35 (br, 1H), 3.05 (br, 1H), 2.93 (t, 2H), 2.32 (m, 1H),2.10-1.70 (m, 4H), 1.38 (t, 3H).

Example 9(R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-[2-(4-nitrophenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 72 mg (26%) as yellow solid. ¹H-NMR (CDCl₃): 8.04 (d, 2H),7.59 (d, 2H), 7.40-7.03 (m, 7H), 6.98 (t, 2H), 5.11 (m, 1H), 4.79 (m,2H), 4.25 (m, 1H), 4.05 (m, 1H), 3.95-3.70 (m, 4H), 3.55 (br, 1H),.3.16(t, 2H), 3.05 (br, 1H), 2.93 (t, 2H), 2.32 (m, 1H), 2.10-1.50 (m, 4H).

Example 10(R)-1-[2-(2,4-Difluorophenylsulfanyl)ethyl]-3-[(4-fluorobenzyl)phenylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 182 mg (64%) as yellow solid. ¹H-NMR (CDCl₃): 7.61 (ddd,1H), 7.40-7.17 (m, 6H), 7.09 (m, 1H), 7.00-6.88 (m, 2H), 6.97 (t, 1H),6.82 (dd, 1H), 5.11 (m, 1H), 4.78 (s, 2H), 4.23 (ddd, 1H), 4.00-3.50 (m,5H), 3.45-3.20 (m, 3H), 2.93 (br, 1H), 2.32 (m, 1H), 2.10-1.80 (m, 3H)1.60 (m, 1H).

Example 11(R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 32 mg (10%) as white solid. IR (film, cm⁻¹): 1703. ¹H-NMR(CDCl₃): 7.40-6.80 (m, 12H), 6.85 (d, 2H), 5.13 (m, 1H), 4.88 (m, 2H),4.18 (m, 1H), 4.05 (t, 2H), 3.90-3.60 (m, 4H), 3.47 (m, 1H), 3.23 (m,1H), 2.80 (m, 1H), 2.40-1.80 (m, 7H).

Example 12(R)-1-Cyclobutylmethyl-3-[(4-fluorobenzyl)-m-tolylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 132 mg (63%) as an oil. ¹H-NMR (CDCl₃): 7.25-7.17 (m, 3H),7.06 (d, 2H), 7.00 (d, 2H), 6.88 (br, 1H), 5.09 (m, 1H), 4.78 (m, 2H),4.10-3.80 (m, 3H), 3.56 (d, 2H), 3.55 (m, 1H), 3.05 (br, 1H), 2.75 (br,1H), 2.35 (m, 1H), 2.32 (s, 3H), 2.10-0.90 (m, 11H).

Example 13(R)-1-[2-(3,4-Dimethoxyphenyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 190 mg (60%) as a white solid. ¹H-NMR (CDCl₃): 7.35-6.92(m, 10H), 6.76 (s, 2H), 5.08 (m, 1H), 4.78 (s, 2H), 4.25-3.60 (m, 6H),3.95 (s, 3H), 3.82 (s, 3H), 3.26 (m, 1H), 2.97 (m, 3H), 2.30 (m, 1H),2.10-1.50 (m, 4H).

Example 14(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(4-methoxyphenyl)-2-oxoethyl]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 47 mg (19%) as a yellow solid. ¹H-NMR (CDCl₃): 8.11 (d,2H), 7.30-6.87 (m, 10H), 5.80-5.50 (m, 2H), 5.15 (m, 1H), 4.78 (m, 2H),4.53 (m, 1H), 4.35-3.90 (m, 3H), 3.82 (s, 3H), 3.55 (m, 1H), 2.86 (m,1H), 2.45-1.80 (m, 4H), 1.60 (m, 1H).

Example 15(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 90 mg (55%) as a brown solid. ¹H-NMR (CDCl₃): 7.35-7.00(m, 9H), 6.97 (t, 2H), 5.30 (m, 2H), 5.11 (m, 1H), 4.76 (m, 2H), 4.43(m, 1H), 4.10-3.80 (m, 4H), 3.49 (m, 1H), 3,20 (br, 1H), 2.33 (m, 1H),2.10-1.55 (m, 4H).

Example 16(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-oxo-2-thiophen-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 101 mg (60%) as a yellow solid. ¹H-NMR (CDCl₃): 8.39 (d,2H), 7.73 (d, 1H), 7.30-7.18 (m, 3H), 7.13 (s, 1H), 7.10-7.05 (m, 3H),6.97 (t, 2H), 5.71 (dd, 2H), 5.15 (m, 1H), 4.78 (dd, 2H), 4.51 (m, 1H),4.35-3.90 (m, 4H), 3.56 (m, 1H), 2.35 (m, 1H), 2.45-1.55 (m, 4H).

Example 17(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(3-methoxyphenoxycarbonylmethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 43 mg (24%) as a yellow solid. ¹H-NMR (CDCl₃): 7.35-7.16(m, 7H), 7.13-7.00 (m, 3H), 6.97 (t, 2H), 5.21-4.90 (m, 3H), 4.85 (d,1H), 4.76 (d, 1H), 4.41 (m, 1H), 4.25-3.60 (m, 4H), 3.76 (s, 3H), 3.53(m, 1H), 2.35 (m, 1H), 2.20-1.70 (m, 3H), 1.60 (m, 1H).

Example 18(R)-1-Cyclopentylcarbamoylmethyl-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 100 mg (39%) as a brown solid. ¹H-NMR (CDCl₃): 8.78 (m,1H), 7.35-7.00 (m, 6H), 6.97 (t, 2H), 5.11 (m, 1H), 4.78 (s, 2H), 4.61(d, 1H), 4.30-3.85 (m, 4H), 4.23 (d, 1H), 3.80-3.60 (m, 3H), 3.21 (m,1H), 2.37 (m, 1H), 2.10-1.40 (m, 12H).

Example 19(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[(2-fluorophenylcarbamoyl)methyl]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 93 mg (60%) as a brown solid. ¹H-NMR (CDCl₃): 10.23 (br,1H), 7.73 (td, 1H), 7.40-6.98 (m, 9H), 6.94 (t, 2H), 5.15 (m, 1H), 5.01(d, 1H), 4.79 (s, 2H), 4.72 (d, 1H), 4.45 (m, 1H), 4.30-3.70 (m, 4H),3.39 (m, 1H), 2.38 (m, 1H), 2.10-1.60 (m, 4H).

Example 20(R)-1-[2-(4-acetylaminophenylsulfanyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 30 mg (9%) as a yellow solid. ¹H-NMR (CDCl₃): 9.52 (s,1H), 7.63 (d, 2H), 7.40-6.94 (m, 9H), 5.10 (m, 1H), 4.73 (s, 2H),4.30-4.00 (m, 2H), 3.95-3.60 (m, 4H), 3.40-3.20 (m, 3H), 2.90 (m, 1H),2.35 (m, 1H), 2.19 (s, 3H), 2.10-1.50 (m, 4H).

Example 21(R)-1-[2-(2,3-Dimethylphenylsulfanyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 94 mg (59%) as a yellow solid. ¹H-NMR (CDCl₃): 7.35-7.00(m, 9H), 6.96 (t, 2H), 5.11 (m, 1H), 4.76 (s, 2H), 4.25-3.90 (m, 3H),3.85-3.40 (m, 3H), 3.40-3.10 (m, 3H), 2.86 (m, 1H), 2.35 (s, 3H), 2.33(m, 1H), 2.30 (s, 3H), 2.20-1.50 (m, 4H).

Example 22(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(1-methyl-1H-imidazol-2-ylsulfanyl)ethyl]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 79 mg (49%) as a brown oil. ¹H-NMR (CDCl₃): 7.67 (d, 1H),7.32-7.05 (m, 6H), 6.97 (t, 2H), 6.73 (d, 1H), 5.13 (m, 1H), 4.77 (s,2H), 4.65 (m, 2H), 4.40-4.10 (m, 2H), 4.10-3.60 (m, 4H), 3.56 (s, 3H),3.12 (m, 1H), 2.85 (m, 1H), 2.31 (m, 1H), 2.20-1.70 (m, 3H), 1.60 (m,1H).

Example 23 (3R,SS) and(3R,SR)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(2-methoxybenzenesulfinyl)ethyl]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 72 mg (47%) as a white solid. ¹H-NMR (CDCl₃): 7.62 (d,1H), 7.52 (t, 1H), 7.35-7.00 (m, 8H), 6.96 (t, 2H), 5.12 (m, 1H), 4.76(s, 2H), 4.20 (m, 1H), 4.10-3.80 (m, 2H), 3.94 (s, 3H), 3.75-3.50 (m,4H), 3.41 (m, 1H), 3.17 (m, 1H), 2.85 (m, 1H), 2.33 (m, 1H), 2.20-1.80(m, 3H), 1.59 (m, 1H).

Example 24(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-methoxyphenylsulfanylcarbonylmethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 66 mg (31%) as a yellow solid. ¹H-NMR (CDCl₃): 7.35-7.00(m, 10H), 6.97 (t, 2H), 5.25-5.05 (m, 3H), 4.77 (dd, 2H), 4.50-3.80 (m,5H), 3.76 (s, 3H), 3.50 (m, 1H), 2.32 (m, 1H), 2.10-1.50 (m, 4H).

Example 25(R)-1-(2-Benzoyloxyethyl)-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 52 mg (30%) as a white solid. ¹H-NMR (CDCl₃): 8.02 (d,2H), 7.62 (t, 1H), 7.48 (t, 2H), 7.30-6.85 (m, 8H), 5.12 (m, 1H),4.80-4.65 (m, 4H), 4.45-3.80 (m, 6H), 3.59 (m, 1H), 3.20 (m, 1H), 2.37(m, 1H), 2.10-1.60 (m, 4H).

Example 26(R)-1-(2-Benzoylaminoethyl)-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 56 mg (39%) as a brownish solid. ¹H-NMR (CDCl₃): 9.38 (s,1H), 8.06 (d, 2H), 7.55-7.30 (m, 4H), 7.30-7.00 (m, 5H), 6.94 (t, 2H),5.09 (m, 1H), 4.74 (s, 2H), 4.10 (m, 1H), 4.05-3.60 (m, 5H), 3.32 (m,1H), 2.95 (m, 1H), 2.40 (m, 2H), 2.27 (m, 1H), 2.10-1.70 (m, 3H), 1.59(m, 1H).

Example 27(R)-1-[2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 56 mg (39%) as a brownish solid. ¹H-NMR (CDCl₃): 7.82-7.70(m, 4H), 7.35-7.00 (m, 6H), 6.96 (t, 2H), 5.13 (m, 1H), 4.77 (s, 2H),4.35-3.80 (m, 8H), 3.40-2.95 (m, 2H), 2.35 (m, 1H), 2.10-1.70 (m, 3H),1.59 (m, 1H).

Example 28(R)-1-(2-Benzenesulfonylaminoethyl)-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 64 mg (39%) as a brownish solid. ¹H-NMR (CDCl₃): 7.90-7.76(m, 3H), 7.47 (dd, 2H), 7.45-7.30 (m, 1H), 7.35 (dd, 1H), 7.25-7.00 (m,4H), 6.93 (t, 2H), 5.03 (m, 1H), 4.75 (dd, 2H), 4.00 (m, 1H), 3.80-3.50(m, 6H), 3.40-3.00 (m, 3H), 2.37 (m, 1H), 2.10-1.60 (m, 4H).

Example 29(R)-1-[3-(2-Cyanophenoxy)propyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 92 mg (55%) as a yellow solid. ¹H-NMR (CDCl₃): 7.54 (m,2H), 7.35-6.90 (m, 10H), 5.17 (m, 1H), 4.78 (s, 2H), 4.35-3.80 (m, 8H),3.31 (m, 1H), 3.01 (m, 1H), 2.45-1.80 (m, 6H), 1.65 (m, 1H).

Example 30(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(3-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 250 mg (47%) as a white solid. ¹H-NMR (CDCl₃): 7.83 (ddd,1H), 7.67 (t, 1H), 7.44 (t, 1H), 7.33-7.00 (m, 7H), 6.96 (t, 2H), 5.16(m, 1H), 4.78 (s, 2H), 4.18 (t, 2H), 4.15-3.60 (m, 6H), 3.25 (m, 1H),2.97 (m, 1H), 2.35-1.80 (m, 6H), 1.63 (m, 1H).

Example 31(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(4-methylpyrimidin-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 25 mg (11%) as a orange solid. ¹H-NMR (CDCl₃): 7.50-6.90(m, 10H), 5.16 (m, 1H), 4.78 (s, 2H), 4.15 (m, 1H), 4.15-3.40 (m, 7H),3.22 (m, 1H), 2.92 (m, 1H), 2.40-1.80 (m, 9H), 1.63 (m, 1H).

Example 32(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(pyridin-2-ylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 24 mg (11%) as a red oil. ¹H-NMR (CDCl₃): 8.41 (ddd, 1H),7.51 (td, 1H), 7.35-6.90 (m, 10H), 5.13 (m, 1H), 4.76 (s, 2H), 4.20-3.55(m, 6H), 3.23 (t, 2H), 3.15 (m, 1H), 2.85 (m, 1H), 2.34 (m, 1H),2.20-1.60 (m, 6H).

Example 33(R)-1-[3-(Benzooxazol-2-ylsulfanyl)propyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 80 mg (35%) as a orange solid. ¹H-NMR (CDCl₃): 7.35-7.00(m, 10H), 6.96 (t, 2H), 5.17 (m, 1H), 4.77 (s, 2H), 4.20 (m, 1H),4.00-3.55 (m, 5H), 3.69 (t, 2H), 3.15 (m, 1H), 2.85 (m, 1H), 2.57 (m,2H), 2.40-1.80 (m, 4H), 1.57 (m, 1H).

Example 34(R)-1-[3-(2-Fluorobenzenesulfonyl)propyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 81 mg (45%) as a brown solid. ¹H-NMR (CDCl₃): 7.89 (td,1H), 7.68 (tdd, 1H), 7.34 (td, 1H), 7.30-7.00 (m, 7H), 6.96 (t, 2H),5.12 (m, 1H), 4.76 (s, 2H), 4.10 (m, 1H), 4.00-3.60 (m, 5H), 3.48 (t,2H), 3.21 (m, 1H), 2.93 (m, 1H), 2.50-1.70 (m, 6H), 1.60 (m, 1H).

Example 35(R)-1-{3-[Acetyl-(3-Chlorophenyl)amino]propyl}-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 23 mg (9%) as a brown solid. ¹H-NMR (CDCl₃): 7.30-7.02 (m,10H), 6.97 (t, 2H), 5.14 (m, 1H), 4.77 (s, 2H), 4.19 (m, 1H), 4.09-3.50(m, 5H), 3.69 (t, 2H), 3.20 (m, 1H), 2.90 (m, 1H), 2.50-1.80 (m, 6H),2.17 (s, 3H), 1.58 (m, 1H).

Example 36(R)-1-{3-[Benzyloxycarbonyl-(2-fluorophenyl)amino]propyl}-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 410 mg (65%) as a white solid. ¹H-NMR (CDCl₃): 7.38-7.02(m, 15H), 6.96 (t, 2H), 5.09 (s, 2H), 5.08 (m, 1H), 4.76 (dd, 2H),4.20-3.30 (m, 6H), 3.72 (t, 2H), 3.05 (m, 1H), 2.77 (m, 1H), 2.27 (m,1H), 2.10-1.80 (m, 5H) 1.56 (m, 1H).

Example 37(R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-phenylcarbamoylethyl)-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 95 mg (66%) as a yellow solid. ¹H-NMR (CDCl₃): 10.95 (s,1H), 7.79 (d, 2H), 7.31-7.00 (m, 9H), 6.95 (t, 2H), 5.11 (m, 1H), 4.75(s, 2H), 4.09 (m, 1H), 3.95-3.10 (m, 6H), 2.87 (m, 1H), 2.29 (m, 1H),2.10-1.70 (m, 5H) 1.58 (m, 1H).

Example 38(R)-1-(3-Benzoyloxypropyl)-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 22 mg (13%) as a yellow solid. ¹H-NMR (CDCl₃): 8.02 (m,2H), 7.56 (m, 1H), 7.45 (m, 2H), 7.30-6.92 (m, 8H), 5.15 (m, 1H), 4.75(s, 2H), 4.43 (m, 2H), 4.15 (m, 1H), 4.05-3.77 (m, 5H), 3.18 (m, 1H),2.87 (m, 1H), 2.42-1.80 (m, 6H), 1.56 (m, 1H).

Example 39(R)-1-[2-(4-acetylaminophenylsulfanyl)ethyl]-3-[(4-fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 99 mg (33%) as a yellow solid. ¹H-NMR (CDCl₃): 9.66 (s,1H), 7.62 (d, 2H), 7.26-7.14 (m, 6H), 7.00-6.90 (m, 6H), 5.05 (m, 1H),4.80 (m, 2H), 4.10 (m, 1H), 3.90-3.40 (m, 6H), 3.10 (m, 3H), 2.30 (m,1H), 2.17 (s, 3H), 2.10-1.50 (m, 4H).

Example 40(3R,2′RS)-3-[(3,4-Difluorobenzyl)phenylcarbamoyloxy]-1-[3-(4-fluorophenoxy)-2-hydroxypropyl]-1-azoniabicyclo[2.2.2]octane;hydroxide

The yield was 18 mg (8%), as a yellow oil. ¹H-NMR (CDCl₃): 7.45-7.80 (m,12H), 6.38 (br, 1H), 5.12 (m, 1H), 4.90-4.58 (m, 3H), 4.35-4.15 (m, 1H),4.10-3.44 (m, 8H), 3.10 (br, 1H), 2.35 (m, 1H), 2.10-1.60 (m, 4H).

Example 41(R)-1-[2-(3-Chloro-5-fluorophenyl)ethyl]-3-[(3,4-difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 101 mg, as a white solid. ¹H-NMR (CDCl₃): 7.67 (m, 1H),7.38-6.85 (m, 9H), 5.17 (m, 1H), 4.76 (s, 2H), 4.33-3.70 (m, 7H), 3.57(m, 1H), 3.33 (m, 1H), 3.17 (m, 2H), 2.99 (m, 1H), 2.35 (m, 1H),2.10-1.80 (m, 3H), 1.60 (m, 1H).

Example 42(R)-1-(2-Cyclohexylsulfanylethyl)-3-[(3,4-difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 58 mg (28%) as a yellow oil. ¹H-NMR (CDCl₃): 7.30 ((m,1H), 7.20-7.00 (m, 5H), 6.95 (m, 1H), 5.13 (m, 1H), 4.75 (s, 2H),4.25-4.25 (m, 2H), 4.00-3.80 (m, 1H), 3.73 (m, 2H), 3.50 (m, 1H), 3.27(m, 1H), 2.88 (m, 4H), 2.35 (m, 1H), 2.10-1.80 (m, 4H) 1.80-1.50 (m,4H), 1.45-1.10 (m, 6H).

Example 43(R)-1-(2-Benzenesulfonylethyl)-3-[(3,4-difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 43 mg (20%) as a yellow oil. ¹H-NMR (CDCl₃): 7.35-6.90 (m,12H), 5.08 (m, 1H), 4.74 (s, 2H), 4.15-3.85 (m, 3H), 3.75-3.45 (m, 4H),3.20-3.05 (m, 1H), 2.95-2.80 (m, 1H), 2.71 (t, 2H), 2.35 (m, 1H),2.10-1.70 (m, 4H).

Example 44(R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 170 mg (63%) as white solid. ¹H-NMR (CDCl₃): 7.58 (s, 2H),7.36-6.94 (m, 10H), 5.57 (m, 2H), 5.06 (m, 1H), 4.74 (s, 2H), 4.13 (m,1H), 4.00-3.40 (m, 6H), 3.10 (br, 1H), 2.32 (m, 1H), 2.32 (s, 3H),2.20-1.50 (m, 4H).

Example 45(R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-[3-(4-fluorophenylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 96 mg (43%) as a green solid. ¹H-NMR (CDCl₃): 7.40 (dd,2H), 7.25-6.80 (m, 9H), 5.09 (m, 1H), 4.72 (m, 2H), 4.11 (m, 1H),3.90-3.60 (m, 5H), 3.27 (m, 1H), 2.96 (t, 2H), 2.64 (m, 1H), 2.31 (m,1H), 2.31 (s, 3H), 2.10-1.70 (m, 5H), 1.55 (m, 1H).

Example 46(R)-3-[(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 145 mg (56%) as a white solid. ¹H-NMR (CDCl₃): 7.37-7.16(m, 3H), 7.15-6.96 (m, 6H), 6.94-6.80 (m, 3H), 5.11 (m, 1H), 4.81 (m,2H), 4.50-4.12 (m, 6H), 4.10-3.70 (m, 3H), 3.45 (br, 1H), 2.32 (m, 1H),2.02 (m, 2H), 1.90-1.60 (m, 2H).

Example 47(R)-3-[(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 151 mg (67%) as a white. ¹H-NMR (CDCl₃): 7.37-6.82 (m,12H), 5.09 (m, 1H), 4.78 (m, 2H), 4.07 (m, 1H), 3.68 (m, 5H), 3.25 (br,1H 3.00 (br, 1H), 2.70 (m, 2H), 2.32 (m, 1H), 2.20-1.60 (m, 6H).

Example 48(R)-1-Cyclopropylmethyl-3-[(2-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 107 mg (54%) as a white solid. ¹H-NMR (CDCl₃): 7.40-7.05(m, 4H), 6.90 (m, 1H), 6.89 (dd, 1H), 5.13 (m, 1H), 4.74 (s, 2H),4.20-3.90 (m, 3H), 3.85-3.60 (m, 2H), 3.55 (m, 2H), 3.38 (m, 1H), 3.09(m, 1H), 2.35 (m, 1H), 2.20-1.85 (m, 3H) 1.54 (m, 1H), 0.93 (m, 1H),0.80 (m, 2H), 0.57 (m, 2H).

Example 49(R)-1-Benzyl-3-[(2-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 119 mg (56%) as a white solid. ¹H-NMR (CDCl₃): 7.55 (m,2H), 7.44 (s, 3H), 7.32-7.05 (m, 4H), 7.00-6.89 (m, 2H), 5.08 (m, 2H),4.91 (m, 1H), 4.69 (s, 2H), 4.07 (m, 4H), 3.77 (m, 2H), 3.32 (br, 1H),2.95 (br, 1H), 2.31 (m, 1H), 2.20-1.45 (m, 4H).

Example 50(R)-3-[(2-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 36 mg (17%) as a yellow solid. ¹H-NMR (CDCl₃): 7.46-7.22(m, 6H), 7.20-7.02 (m, 3H), 6.96-6.83 (m, 2H), 5.12 (m, 1H), 4.73 (s,2H), 4.25-3.95 (m, 3H), 3.80-3.50 (m, 3H), 3.45-3.20 (m, 3H), 2.90 (br,1H), 2.33 (m, 1H), 2.10-1.80 (m, 3H), 1.59 (m, 1H).

Example 51(R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 126 mg (55%) as a white solid. ¹H-NMR (CDCl₃): 7.40-7.21(m, 3H), 7.10-6.80 (m, 9H), 5.13 (m, 1H), 4.82 (m, 2H), 4.16 (m, 1H),4.06 (t, 2H), 4.00-3.60 (m, 6H), 3.30 (br, 1H), 2.38 (m, 1H), 2.25 (m,2H), 2.15-1.60 (m, 4H).

Example 52(R)-1-[3-(3,4-Difluorophenoxy)propyl]-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;chloride

¹H-NMR (CDCl₃): 7.33 (m, 1H), 7.12-6.85 (m, 6H), 6.69 (ddd, 1H), 6.57(m, 1H), 5.16 (m, 1H), 4.83 (m, 2H), 4.18 (m, 1H), 4.04 (t, 2H),4.00-3.60 (m, 6H), 3.30 (br, 1H), 2.38 (m, 1H), 2.34 (m, 2H), 2.15-1.60(m, 4H).

Example 53(R)-1-(2-Oxo-2-phenylethyl)-3-(thiophen-2-ylmethyl-m-tolylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 23 mg (15%) as a white solid. ¹H-NMR (CDCl₃): 8.09 (d,2H), 7.56 (t, 1H), 7.42 (t, 2H), 7.23 (dd, 1H), 7.21 (s, 1H), 7.13-6.96(m, 3H), 6.93-6.83 (m, 2H), 5.79 (s, 2H), 5.15 (m, 1H), 4.95 (m, 2H),4.60-3.80 (m, 4H), 3.61 (m, 1H), 3.29 (m, 1H), 2.33 (m, 1H), 2.32 (s,3H), 2.20-1.50 (m, 4H).

Example 54(R)-1-(3-Phenylpropyl)-3-(thiophen-2-ylmethyl-m-tolylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 36 mg (23%) as a white solid. ¹H-NMR (CDCl₃): 7.34-7.18(m, 5H), 7.08 (d, 1H), 7.01 (d, 1H), 6.94-6.82 (m, 5H), 5.11 (m, 1H),4.92 (s, 2H), 4.45-3.90 (m, 6H), 3.85-3.60 (m, 2H), 3.15 (m, 1H), 3.01(m, 1H), 2.41 (m, 1H), 2.31 (s, 3H), 2.20-1.61 (m, 4H).

Example 55(R)-1-Benzyl-3-[(2-fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 163 mg (75%) as a yellow solid. ¹H-NMR (CDCl₃): 7.75-7.35(m, 5H), 7.25-6.82 (m, 7H), 5.12 (m, 1H), 5.20-4.80 (m, 5H), 4.40-3.40(m, 4H), 3.19 (m, 1H), 3.01 (t, 2H), 2.79 (m, 1H), 2.27 (m, 1H),2.20-1.50 (m, 4H).

Example 56(R)-1-Cyclobutylmethyl-3-[(3-fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 153 mg (72%) as an oil. ¹H-NMR (CDCl₃): 7.33 (td, 1H),7.25 (dd, 1H), 7.05-6.88 (m, 5H), 5.15 (m, 1H), 5.00 (m, 2H), 4.15-4.00(m, 1H), 3.80-3.95 (m, 2H), 3.70-3.50 (m, 1H), 3.60 (dd, 2H), 3.30 (m,1H), 2.73 (m, 1H), 2.42 (m, 1H), 2.20-0.90 (m, 11H).

Example 57(R)-3-[(3-Methylthiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 170 mg (56%) as an oil. ¹H-NMR (CDCl₃): 7.35-7.25 (m, 1H),7.32 (t, 2H), 7.10-6.80 (m, 6H), 6.58 (m, 1H), 6.51 (m, 1H), 5.13 (m,1H), 4.87 (m, 2H), 4.55-4.30 (m, 3H), 4.30-4.00 (m, 4H), 3.80 (m, 2H),3.15 (br, 1H), 2.42 (m, 1H), 2.41 (s, 3H), 2.20-1.50 (m, 4H).

Example 58(R)-3-[(4-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-Cyclopropylmethyl-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 90 mg (60%) as a white solid. ¹H-NMR (CDCl₃): 7.43-7.28(m, 3H), 7.28-7.10 (m, 2H), 7.15 (d, 1H), 6.83 (s, 1H), 5.12 (m, 1H),4.91 (m, 2H), 4.17 (ddd, 1H), 4.05-3.30 (m, 4H), 3.57 (d, 2H), 2.93 (br,1H), 2.35 (m, 1H), 2.20-1.50 (m, 4H), 0.97 (br, 1H), 0.78 (m, 2H), 0.56(m, 2H).

Example 59(R)-3-[(4-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-phenylsulfanylmethyl-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 89 mg (57%) as a white solid. ¹H-NMR (CDCl₃): 7.68 (m,1H), 7.58 (br, 3H), 7.45-7.30 (m, 6H), 7.13 (m, 2H), 6.81 (s, 1H), 5.54(m, 2H), 5.07 (m, 1H), 4.90 (m, 2H), 4.12 (m, 1H), 3.90-3.60 (m, 3H),3.45 (m, 1H), 3.11 (m, 1H), 2.33 (m, 1H), 2.20-1.50 (m, 4H).

Example 60(R)-1-[2-(2,3-Dihydrobenzofuran-5-yl)ethyl]-3-[(5-methylthiophen-2-ylmethyl)phenylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 310 mg (63%) as a white solid. ¹H-NMR (CDCl₃): 7.36-7.05(m, 5H), 7.29 (d, 1H), 7.15 (s, 1H), 6.93 (d, 1H), 6.61 (d, 1H), 6.54(d, 1H), 5.08 (m, 1H), 4.83 (m, 2H), 4.47 (t, 2H), 4.13 (ddd, 1H),4.09-3.80 (m, 2H), 3.80-3.50 (m, 3H), 3.20 (br, 1H), 3.09 (t, 2H), 2.89(t, 2H), 2.85 (br, 1H), 2.39 (s, 3H), 2.29 (m, 1H), 2.21-1.80 (m, 4H),1.52 (br, 1H).

Example 61(R)-3-[(5-Chlorothiophen-2-ylmethyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 200 mg (98%) as a yellow solid. ¹H-NMR (CDCl₃): 7.40-7.20(m, 4H), 7.15-6.95 (m, 3H), 6.95-6.80 (m, 2H), 6.69 (br, 1H), 6.61 (br,1H), 5.13 (m, 1H), 4.80 (s, 2H), 4.60-4.00 (m, 8H), 3.53 (m, 1H), 3.06(m, 1H), 2.40 (m, 1H), 2.20-1.50 (m, 4H).

Example 62(R)-3-[(5-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-Cyclopropylmethyl-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 100 mg (60%) as a white solid. ¹H-NMR (CDCl₃): 7.45-7.25(m, 3H), 7.25-7.09 (m, 2H), 6.87 (d, 1H), 6.64 (br, 1H), 5.12 (m, 1H),4.89 (m, 2H), 4.40 (m, 1H), 4.17 (m, 1H), 4.05-3.80 (m, 2H), 3.80-3.05(m, 6H), 2.36 (m, 1H), 2.20-1.50 (m, 4H), 0.95 (m, 1H), 0.81 (m, 2H),0.58 (m, 2H).

Example 63(R)-3-[(5-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 50 mg (28%) as a white solid. ¹H-NMR (CDCl₃): 7.47-7.20(m, 8H), 7.13 (br, 2H), 6.85 (d, 1H), 6.62 (d, 1H), 5.11 (m, 1H), 4.84(s, 2H), 4.15 (m, 1H), 4.00 (m, 2H), 3.85-3.50 (m, 4H), 3.45-3.20 (m,2H), 2.95 (br, 1H), 2.33═(m, 1H), 2.20-1.80 (m, 3H), 1.62 (m, 1H).

Example 64(R)-3-[(5-Bromothiophen-2-ylmethyl)-m-tolylcarbamoyloxy]-1-phenylsulfanylmethyl-1-azoniabicyclo[2.2.2]octane;chloride

The yield was 83 mg (79%) as a yellow solid. ¹H-NMR (CDCl₃): 7.58 (m,2H), 7.46-7.31 (m, 3H), 7.21 (d, 1H), 7.12 (m, 1H), 7.02-6.86 (m, 2H),6.86 (d, 1H), 6.64 (m, 1H), 5.55 (m, 2H), 5.07 (m, 1H), 4.83 (s, 2H),4.15-3.60 (m, 4H), 3.40 (br, 1H), 3.05 (br, 1H), 2.34 (s, 3H), 2.33 (m,1H), 2.20-1.50 (m, 4H).

Example 65(R)-3-[(5-Bromothiophen-2-ylmethyl)-(4-fluorophenyl)carbamoyloxy]-1-cyclopropylmethyl-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 81 mg (62%) as a brownish solid. ¹H-NMR (CDCl₃): 7.32-7.12(m, 2H), 7.04 (t, 2H), 6.87 (d, 1H), 6.63 (m, 1H), 5.11 (m, 1H),5.05-4.60 (m, 2H), 4.15 (m, 1H), 4.00-3.70 (m, 3H), 3.65-3.45 (m, 3H),3.15 (br, 1H), 2.37 (m, 1H), 2.15-1.55 (m, 4H), 0.98 (m, 1H), 0.80 (m,2H), 0.59 (m, 2H).

Example 66(R)-3-[(5-Bromothiophen-2-ylmethyl)-(4-fluorophenyl)carbamoyloxy]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 110 mg (76%) as a yellow solid. ¹H-NMR (CDCl₃): 8.12 (d,2H), 7.58 (t, 1H), 7.42 (t, 2H), 7.36-7.24 (m, 2H), 7.03 (t, 2H), 6.86(d, 1H), 6.63 (m, 1H), 5.85 (s, 2H), 5.18 (m, 1H), 5.00 (m, 1H),4.75-3.90 (m, 6H), 3.66 (m, 1H), 2.35 (m, 1H), 2.15-1.55 (m, 4H).

Example 67(R)-3-[(5-Bromothiophen-2-ylmethyl)(4-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 107 mg (73%) as a yellow solid. ¹H-NMR (CDCl₃): 7.33-7.15(m, 7H), 7.02 (t, 2H), 6.84 (d, 1H), 6.61 (m, 1H), 5.09 (m, 1H),5.02-4.60 (m, 2H), 4.12 (m, 1H), 3.80-3.55 (m, 5H), 3.45 (br, 1H), 3.10(br, 1H), 2.70 (t, 2H), 2.50-1.75 (m, 7H), 1.60 (m, 1H).

Example 68(R)-1-Cyclobutylmethyl-3-[(3-fluorophenyl)thiophen-3-ylmethylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 89 mg (42%) as white solid. ¹H-NMR (CDCl₃): 7.40-7.30 (m,3H), 7.16 (s, 1H), 7.03-6.87 (m, 3H), 5.11 (m, 1H), 4.86 (m, 2H), 4.08(m, 1H), 3.90-3.70 (m, 2H), 3.70-3.50 (m, 1H), 3.59 (d, 2H), 3.35 (m,1H), 3.02 (m, 1H), 2.72 (m, 1H), 2.36 (m, 1H), 2.20-0.90 (m, 11H).

Example 69(R)-3-[(3-Fluorophenyl)thiophen-3-ylmethylcarbamoyloxy]-1(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 161 mg (68%) as a white solid. ¹H-NMR (CDCl₃): 8.10 (d,2H), 7.56 (t, 1H), 7.43 (t, 2H), 7.32-7.18 (m, 3H), 7.14 (m, 1H),7.05-6.85 (m, 3H), 5.86 (s, 2H), 5.16 (m, 1H), 4.77 (m, 2H), 4.60-3.90(m, 5H), 3.70 (m, 1H), 2.34 (m, 1H), 2.20-1.50 (m, 4H).

Example 70(R)-3-Cyclohexylmethylphenylcarbamoyloxy-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 120 mg (75%) as an oil. ¹H-NMR (CDCl₃): 8.10 (d, 2H), 7.58(t, 1H), 7.43 (t, 2H), 7.40-7.20 (m, 5H), 5.75 (s, 2H), 5.09 (m, 1H),4.51-3.90 (m, 5H), 3.55 (d, 2H), 2.95 (br, 1H), 2.35 (m, 1H), 2.15-0.90(m, 15H).

Example 71(R)-3-Cyclohexylmethylphenylcarbamoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The yield was 40 mg (35%) as an oil. ¹H-NMR (CDCl₃): 7.34 (t, 2H),7.30-7.15 (m, 4H), 7.05 (t, 2H), 6.88 (d, 2H), 5.07 (m, 1H), 4.55-3.90(m, 6H), 3.87-3.60 (m, 3H), 3.48 (d, 2H), 2.95 (br, 1H), 2.35 (m, 1H),2.15-0.90 (m, 15H).

The following compounds were also prepared, and they have beenidentified by ¹H-NMR:

-   (R)-3-(Benzylphenylcarbamoyloxy)-1-Cyclopropylmethyl-1-azoniabicyclo[2.2.2]octane,    bromide-   (R)-3-(Benzylphenylcarbamoyloxy)-1-Cyanomethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-Benzyl-3-(benzylphenylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-(Benzylphenylcarbamoyloxy)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-(Benzylphenylcarbamoyloxy)-1-(4-methoxybenzyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-(Benzylphenylcarbamoyloxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-(Benzylphenylcarbamoyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-(Benzylphenylcarbamoyloxy)-1-[2-(4-fluorophenoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-(Benzylphenylcarbamoyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-(Benzylphenylcarbamoyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-(Benzylphenylcarbamoyloxy)-1-[3-(4-fluorophenoxy)-2-hydroxypropyl]-1-azoniabicyclo[2.2.2]octane;    hydroxide-   (R)-1-Cyclobutylmethyl-3-[(4-fluorobenzyl)phenylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-Benzyl-3-[(4-fluorobenzyl)phenylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-phenylsulfanylmethyl-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-(2-o-tolylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-[2-(2-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-[2-(3-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-[2-(3-fluorophenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-(2-p-tolylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-[2-(4-fluorophenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(2,5-Dimethoxyphenyl)ethyl]-3-[(4-fluorobenzyl)phenylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(3,4-Dimethoxyphenyl)ethyl]-3-[(4-fluorobenzyl)phenylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide.-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-[2-(4-fluorophenoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)phenylcarbamoyloxy]-1-[2-(2-fluorophenylsulfanyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-m-tolylcarbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(2,3-Dihydrobenzofuran-5-yl)ethyl]-3-[(4-fluorobenzyl)-m-tolylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-m-tolylcarbamoyloxy]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-m-tolylcarbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-m-tolylcarbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-m-tolylcarbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-phenylsulfanylmethyl-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-o-tolylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(2-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-m-tolylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(3-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(3-fluorophenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-p-tolylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(4-Ethoxyphenyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(4-fluorophenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(2,5-Dimethoxyphenyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-phenylcarbamoylmethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(o-tolylcarbamoylmethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(2-fluorophenoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(3-methoxyphenoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(4-fluorophenoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(2-metoxyphenylsulfanyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(2-fluorophenylsulfanyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[2-(2-Chlorophenylsulfanyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[2-(3-Chlorophenylsulfanyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(4-fluorophenylsulfanyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[2-(4-Bromophenylsulfanyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[2-(2,4-Difluorophenylsulfanyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(2,5-Dichlorophenylsulfanyl)ethyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (3R,SS) and    (3,SR)-1-(2-Benzenesulfinylethyl)-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(2-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(3-m-tolyloxypropyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(3-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[3-(2,4-Difluorophenoxy)propyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(pyridin-3-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(pyrimidin-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane.-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(2-fluorophenylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[3-(2-Chlorophenylsulfanyl)propyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[3-(3-Chlorophenylsulfanyl)propyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(pyridin-4-ylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane-   (R)-3-[(4-Fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(pyrimidin-2-ylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane-   (R)-1-(3-Benzenesulfonylpropyl)-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[3-(3-Chlorobenzenesulfonyl)propyl]-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-{3-[Acetyl-(2-fluorophenyl)amino]propyl}-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-{3-[Acetyl-(3-methoxyphenyl)amino]propyl}-3-[(4-fluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-Benzyl-3-[(4-fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-phenylsulfanylmethyl-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[2-(2-Chlorophenyl)ethyl]-3-[(4-fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-[2-(3-fluorophenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-[2-(4-fluorophenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(2-Chloro-6-fluorophenyl)ethyl]-3-[(4-fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[3-(3,4-Difluorophenoxy)propyl]-3-[(4-fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[3-(3-Chlorophenylsulfanyl)propyl]-3-[(4-fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Fluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-[3-(4-fluorophenylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[2-(4-fluorophenoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (3R,2′RS)-3-[(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(4-fluorophenoxy)-2-hydroxypropyl]-1-azoniabicyclo[2.2.2]octane;    hydroxide-   (R)-3-[(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(2-fluorophenyl)carbamoyloxy]-1-[3-(2,4-difluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-[2-(2-fluorophenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-[2-(4-fluorophenoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3,4-Difluorobenzyl)-m-tolylcarbamoyloxy]-1-[3-(2-fluorophenylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[3-(3-Chlorophenylsulfanyl)propyl]-3-[(3,4-difluorobenzyl)-m-tolylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-Cyclopropylmethyl-3-[(3,4-difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-[2-(4-fluorophenoxy)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3,4-Difluorobenzyl)-(3-fluorophenyl)carbamoyloxy]-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(2-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(2-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(2-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(4-Fluorophenoxy)ethyl]-3-[(2-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(2-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(2-Fluorophenyl)ethyl]-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-1-[2-(2,3-Dihydrobenzofuran-5-yl)ethyl]-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(4-Fluorophenoxy)ethyl]-3-[(3-fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3-Fluorophenyl)-(3,4,5-trifluorobenzyl)carbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-Cyclobutylmethyl-3-(thiophen-2-ylmethyl-m-tolylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-Phenethyl-3-(thiophen-2-ylmethyl-m-tolylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(2,3-Dihydrobenzofuran-5-yl)ethyl]-3-(thiophen-2-ylmethyl-m-tolylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-(2-Thiophen-2-ylethyl)-3-(thiophen-2-ylmethyl-m-tolylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-(3-Phenoxypropyl)-3-(thiophen-2-ylmethyl-m-tolylcarbamoyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-Cyclopropylmethyl-3-[(2-fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(2-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(2-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(2-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(2-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(2-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(2-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-Benzyl-3-[(3-fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-phenylsulfanylmethyl-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(3-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-[2-(4-methoxyphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-[1-[2-(2,3-Dihydrobenzofuran-5-yl)ethyl]-3-[(3-fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3-Fluorophenyl)thiophen-2-ylmethylcarbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(4-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(4-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(5-Methylthiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(5-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-phenylsulfanylmethyl-1-azoniabicyclo[2.2.2]octane;    chloride-   (R)-3-[(5-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(5-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(5-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(5-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(5-Bromothiophen-2-ylmethyl)phenylcarbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(5-Bromothiophen-2-ylmethyl)-m-tolylcarbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(5-Bromothiophen-2-ylmethyl)-m-tolylcarbamoyloxy]-1-(2-phenylsulfanylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(5-Bromothiophen-2-ylmethyl)-m-tolylcarbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3-Fluorophenyl)thiophen-3-ylmethylcarbamoyloxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-1-[2-(2,3-Dihydrobenzofuran-5-yl)ethyl]-3-[(3-fluorophenyl)thiophen-3-ylmethylcarbamoyloxy]-1-azoniabicyclo[2.2.2]octane;    bromide-   (R)-3-[(3-Fluorophenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane-   (R)-3-[(3-Fluorophenyl)thiophen-3-ylmethylcarbamoyloxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide

1. A compound of general formula (I)

and individual isomers, racemic or non-racemic mixtures of isomers, andpharmaceutically acceptable salts thereof, wherein R1, R2 and R3 areradicals independently selected from the group consisting of H, OH, NO₂,SH, CN, F, Cl, Br, I, COOH, CONH₂, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl,(C₁-C₄)-alkoxyl optionally substituted with one or several F, and(C₁-C₄)-alkyl optionally substituted with one or several F or OH;alternatively, either R1 and R2, or R2 and R3 may be forming a biradicalselected from the group consisting of —CH₂—CH₂—CH₂—, and—CH₂—CH₂—CH₂—CH₂—; R4 is a radical selected from the group consistingof: a) a C-linked radical of a five or six membered heterocyclic ringcontaining at least one heteroatom selected from the group consisting ofO, S, and N, being this heterocyclic ring substituted with one orseveral substituents independently selected from the group consisting ofOH, oxo (═O), SH, NO₂, CN, F, Cl, Br, I, CONH₂, COOH,(C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl,(C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionally substituted with one orseveral F or OH, and (C₁-C₄)-alkoxyl optionally substituted with one orseveral F; b) a C-linked radical of a bicyclic ring system consisting ofa phenyl ring fused to a five or six membered heterocyclic ringcontaining at least one heteroatom selected from the group consisting ofO, S and N, being this bicyclic ring system optionally substituted withone or several substituents independently selected from the groupconsisting of OH, oxo (═O), SH, NO₂, CN, F, Cl, Br, I, CONH₂, COOH,(C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl,(C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionally substituted with one orseveral F or OH, and (C₁-C₄)-alkoxyl optionally substituted with one orseveral F; and c) phenyl substituted with one or several substituentsindependently selected from the group consisting of OH, SH, NO₂, CN, F,Cl, Br, I, CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,(C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionallysubstituted with one or several F or OH, and (C₁-C₄)-alkoxyl optionallysubstituted with one or several F; R5 is a radical selected from thegroup consisting of: a) cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, all of them optionally substituted with one or severalsubstituents independently selected from the group consisting of OH, oxo(═O), SH, NO₂, CN, F, Cl, Br, I, CONH₂, NR7CO—(C₁-C₄)-alkyl, COOH,(C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl,(C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionally substituted with one orseveral F or OH, and (C₁-C₄)-alkoxyl optionally substituted with one orseveral F; b) (C₁-C₁₀)-alkyl substituted with one or several radicalsindependently selected from the group consisting of R6, COR6, NH₂,NR6R7, CONR6R7, NR7COR6, OH, OR6, COOR6, OCOR6, SO₂R6, SH, SR6, SOR6,COSR6, SCOR6, CN, F, Cl, Br, NO₂, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, norbornenyl, and bicyclo[2.2. 1] heptanyl; R6is a radical selected from the group consisting of: a) (C₁-C₅)-alkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,norbomenyl, bicyclo[2.2.1]heptanyl, all of them optionally substitutedwith one or several substituents independently selected from the groupconsisting of OH, oxo (═O), SH, NO₂, CN, F, Cl, Br, I, CONH₂,NR7CO—(C₁-C₄)-alkyl, COOH, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl,(C₁-C₄)-alkyl optionally substituted with one or several F or OH, and(C₁-C₄)-alkoxyl optionally substituted with one or several F; b) phenyloptionally substituted with one or several substituents independentlyselected from the group consisting of OH, SH, NO₂, CN, F, Cl, Br, I,CONH₂, NR7CO—(C₁-C₄)-alkyl, COOH, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl,(C₁-C₄)-alkyl optionally substituted with one or several F or OH, and(C₁-C₄)-alkoxyl optionally substituted with one or several F; c) aC-linked radical of a five or six membered heterocyclic ring containingat least one heteroatom selected from the group consisting of O, S, andN, being this heterocyclic ring optionally substituted with one orseveral substituents independently selected from the group consisting ofOH, oxo (═O), SH, NO₂, CN, F, Cl, Br, I, CONH₂, NR7CO—(C₁-C₄)-alkyl,COOH, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,(C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionallysubstituted with one or several F or OH, and (C₁-C₄)-alkoxyl optionallysubstituted with one or several F; and d) a C-linked radical of abicyclic ring system consisting of a phenyl ring fused to a five or sixmembered heterocyclic ring containing at least one heteroatom selectedfrom the group consisting of O, S and N, being this bicyclic ring systemoptionally substituted with one or several substituents independentlyselected from the group consisting of OH, oxo (═O), SH, NO₂, CN, F, Cl,Br, I, CONH₂, COOH, NR7CO—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl,(C₁-C₄)-alkyl optionally substituted with one or several F or OH, and(C₁-C₄)-alkoxyl optionally substituted with one or several F; R7 is aradical selected from the group consisting of H, phenoxycarbonyl,benzyloxycarbonyl, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylcarbonyl,(C₁-C₄)-alkylsulfonyl, and (C₁-C₅)-alkyl; and X⁻is a physiologicallyacceptable anion.
 2. A compound according to claim 1, wherein R4 is athiophene substituted with one or several substituents independentlyselected from the group consisting of OH, SH, NO₂, CN, F, Cl, Br, I,CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,(C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionallysubstituted with one or several F or OH, and (C₁-C₄)-alkoxyl optionallysubstituted with one or several F.
 3. A compound according to claim 1,wherein R4 is a phenyl substituted with one or several substituentsindependently selected from the group consisting of OH, SH, NO₂, CN, F,Cl, Br, I, CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)-alkylsulfanyl,(C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionallysubstituted with one or several F or OH, and (C₁-C₄)-alkoxyl optionallysubstituted with one or several F.
 4. A compound according to claim 1,wherein R5 is a (C₁-C₅)-alkyl substituted with one radical selected fromthe group consisting of R6, COR6, NR6,R7, CONR6,R7, NR7COR6, OR6, COOR6,OCOR6, SR6, SOR6, SO₂R6; and R6 is a radical selected from the groupconsisting of: a) phenyl optionally substituted with one or severalsubstituents selected from the group consisting of OH, SH, CN, F, Cl,Br, I, CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl, (C₁-C₄)alkylsulfanyl,(C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl, (C₁-C₄)-alkyl optionallysubstituted with one or several F or OH, and (C₁-C₄)-alkoxyl optionallysubstituted with one or several F; b) a C-linked radical of a five orsix membered heterocyclic ring containing at least one heteroatomselected from the group consisting of O, S, and N, being thisheterocyclic ring optionally substituted with one or severalsubstituents independently selected from the group consisting of OH, SH,NO₂, CN, F, Cl, Br, I, CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl,(C₁-C₄)-alkyl optionally substituted with one or several F or OH, and(C₁-C₄)-alkoxyl optionally substituted with one or several F. 5.Intermediate compound of formula (X)

and individual isomers, racemic or non-racemic mixtures of isomers, andpharmaceutically acceptable salts thereof, for the preparation of acompound of formula (I) as defined in claim 1, wherein R1, R2, R3, R8and R9 are radicals independently selected from the group consisting ofH, OH, NO₂, SH, CN, F, Cl, Br, I, CONH₂, COOH, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄)-alkylsulfanyl, (C₁-C₄)-alkylsulfinyl, (C₁-C₄)-alkylsulfonyl,(C₁-C₄)-alkoxyl optionally substituted with one or several F, and(C₁-C₄)-alkyl optionally substituted with one or several F or OH, exceptwhen R8 and R9 are H; alternatively, either R1 and R2, or R2 and R3 maybe forming a biradical selected from the group consisting of—CH₂—CH₂—CH₂—, and —CH₂—CH₂—CH₂—CH₂—.
 6. A compound according to claim1, wherein the configuration of the 3 position in the quinuclidine ringis (R).
 7. A method of treating urinary incontinence in a subjectcomprising administering to the subject in need thereof a therapeuticamount of a compound according to claim
 1. 8. The method according toclaim 7, wherein urinary incontinence is caused by overactive bladder.9. A method of treating irritable bowel syndrome in a subject comprisingadministering to the subject in need thereof a therapeutic amount of acompound according to claim
 1. 10. A method of treating a respiratorydisease in a subject comprising administering to the subject in needthereof a therapeutic amount of a compound according to claim 1, whereinthe disease is selected from the group consisting of chronic obstructivepulmonary disease, chronic bronchitis, asthma, emphysema, and rhinitis.11. A method of treating an ophthalmic intervention in a subjectcomprising administering to the subject in need thereof a therapeuticamount of a compound according to claim 1, wherein administrationinduces mydriasis and cycloplegia.
 12. A pharmaceutical compositioncomprising an effective amount of a compound of claim 1 and apharmaceutically acceptable excipient.